F. M. Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Endo et al in U.S. Pat. Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin I. 1165 (1976)) to have a complex mevalonolactone structure.
GB 1,586,152 discloses a group of synthetic compounds of the formula ##STR3## in which E represents a direct bond, a C.sub.1-3 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U.S. Pat. No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure ##STR4## wherein A is H or methyl; E is a direct bond, --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--; R.sub.1, R.sub.2 and R.sub.3 are each selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, phenyl, phenyl substituted by halogen, C.sub.1-4 alkoxy, C.sub.2-8 alkanoyloxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, and OR.sub.4 in which R.sub.4 is H, C.sub.2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C.sub.1-3 alkyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 -alkyl, adamantyl-C.sub.1-3 -alkyl, or substituted phenyl C.sub.1-3 -alkyl in each of which the substituents are selected from halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C.sub.1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C.sub.1-3 -alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula.
WO 84/02131 (PCT/EP83/00308) (based on U.S. application Ser. No. 443,668, filed Nov. 22, 1982, now abandoned, and U.S. application Ser. No. 548,850, filed Nov. 4, 1983, now abandoned), filed in the name of Sandoz AG discloses heterocyclic analogs of mevalono lactone and derivatives thereof having the structure ##STR5## wherein one of R and R.sub.o is ##STR6## and the other is primary or secondary C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or phenyl--(CH.sub.2).sub.m --,
wherein R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and
m is 1, 2 or 3,
with the provisos that both R.sub.5 and R.sub.5a must be hydrogen when R.sub.4 is hydrogen, R.sub.5a must be hydrogen when R.sub.5 is hydrogen, not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy,
R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R.sub.3 must be hydrogen when R.sub.2 is hydrogen, not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy.
X is --(CH.sub.2).sub.n -- or --CH.dbd.CH-- (n=0, 1, 2 or 3), ##STR7## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl in free acid form or in the form of a physiologically-hydrolysable and -acceptable ester or a .delta. lactone thereof or in salt form.
GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure ##STR8## wherein R.sub.1 =1-3C alkyl;
Z is a gp. of formula Z.sub.1 or Z.sub.2 : ##STR9##
R.sub.7 =H, a hydrolysable ester gp. or a cation.
European Patent No. 164-698-A discloses preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulphonyl halide R.sup.5 SO.sub.2 X, then removing the protecting group Pr, ##STR10## wherein X=halo;
Pr=a carbinol-protecting group;
R.sup.1 =H or CH.sub.3 ;
R.sup.3, R.sup.4 =H, 1-3C alkyl or phenyl-(1-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo;
R.sup.2 =a group of formula (A) or (B): ##STR11##
R.sup.6 =H or OH;
R=H or CH.sub.3 ;
a, b, c and d=optional double bonds;
R.sup.7 =phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo;
R.sup.8, R.sup.9 =1-3C alkyl or halo;
R.sup.5 =1-3C alkyl, phenyl or mono- or di-(1-3C alkyl)phenyl.
Anderson, Paul Leroy, Ger. Offen. DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure ##STR12## wherein R.sup.1 is alkyl, Z=Q, Q.sup.1 ; R.sup.7 =H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
WO 8402-903 (based on U.S. application Ser. No. 460,600, filed Jan. 24, 1983, now abandoned) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure ##STR13## wherein the two groups Ro together form a radical of formula ##STR14## wherein R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy,
R.sub.1 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro or benzyloxy,
R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and with the provisos that not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, ##STR15## wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, Z is ##STR16## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl, with the general proviso that --X--Z and the R.sub.4 bearing phenyl group are ortho to each other;
in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a .delta. lactone thereof or in salt form.
European patent application 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5-thia-.omega.-aryl-alkanoic acids having the structural formula: ##STR17## wherein Z is: ##STR18##
n is 0, 1 or 2;
E is --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH--CH.sub.2 --; or --CH.sub.2 --CH.dbd.CH--;
R.sub.1, R.sub.2 and R.sub.3 are, e.g., hydrogen, chloro, bromo, fluoro, C.sub.1 -alkyl, phenyl, substituted phenyl or OR.sub.7 in which R.sub.7 is, e.g., hydrogen,
C.sub.2-8 alkanoyl, benzoyl, phenyl, substituted phenyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 alkyl, adamantyl-C.sub.1-3 -alkyl, or phenyl C.sub.1-3 alkyl;
R.sup.4, R.sup.5 and R.sup.6 are hydrogen, chloro, bromo, fluoro or C.sub.1-3 alkyl; and
X is, e.g., hydrogen, C.sub.1-3 alkyl, a cation derived from an alkali metal or is ammonium.
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity.
French patent application 2,596,393 A filed on April 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: ##STR19## wherein R.sub.1 and R.sub.2 =H, lower alkyl or optionally substituted aralkyl;
R.sub.3 and R.sub.4 =H, lower alkyl or optionally substituted aryl or aralkyl.
These comounds are disclosed as giving greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol.
European patent application 142,146-A (Merck & Co., Inc) discloses mevinolin-like compounds of the structural formula: ##STR20## wherein:
R.sup.1 is, e.g., hydrogen or C.sub.1-4 alkyl;
E is --CH.sub.2 CH.sub.2, --CH.dbd.CH--, or --(CH.sub.2).sub.r --; and
Z is
(1) ##STR21## wherein X is --O-- or --NR.sup.9 wherein R.sup.9 is hydrogen or C.sub.1-3 alkyl;
R.sup.7 is C.sub.2-8 alkyl; and
R.sup.8 is hydrogen or CH.sub.3 ;
(2) ##STR22## wherein R.sup.10, R.sup.11 and R.sup.12 are independently, e.g., hydrogen, halogen or C.sub.1-4 alkyl;
(3)